Effect of rate of administration on subjective and physiological effects of intravenous cocaine in humans

The rate hypothesis of psychoactive drug action holds that the faster a drug reaches the brain and starts to act, the greater its reinforcing effects and abuse liability. A previous human study using a single cocaine dose confirmed the rate hypothesis for subjective responses, but found no rate effect on cardiovascular responses. We evaluated the rate hypothesis in 17 experienced cocaine users (7 [all men] provided complete data; 6 participated in only 1-2 sessions) by administering IV cocaine at each of three doses (10, 25, 50 mg) and injection durations (10, 30, 60 s) in a double-blind, placebo-controlled, escalating dose design. Heart rate, blood pressure, and positive (e.g., rush, high) and negative (e.g., feel bad, anxious) subjective effects (100-mm visual analogue scales) were measured for 1h after dosing. Peak change from baseline, time to peak, and area under the time-response curve were evaluated with repeated measures mixed linear regression analyses, allowing use of data from all sessions for all subjects, including non-completers. Both dose (mg) and infusion rate (mg/s) significantly influenced most subjective and cardiovascular variables. Analysis of the interaction suggested that dose had a stronger impact than rate. Rate had a stronger influence on positive subjective effects than on negative subjective effects or cardiovascular variables. These findings provide support for the rate hypothesis as it applies to both subjective and cardiovascular effects of IV cocaine administration in humans.     

Minocycline attenuates subjective rewarding effects of dextroamphetamine in humans

Rationale  

Minocycline, a tetracycline antibiotic, interacts with brain glutamate and dopamine neurotransmission. In preclinical studies, minocycline attenuated amphetamine-induced acute dopamine release and subsequent behavioral sensitization. The goal of this study was to determine minocycline’s effects on the acute physiological, behavioral, and subjective responses to dextroamphetamine (DAMP) in healthy volunteers.     

Transdermal nicotine maintenance attenuates the subjective and reinforcing effects of intravenous nicotine, but not cocaine or caffeine, in cigarette-smoking stimulant abusers.

The effects of transdermal nicotine maintenance on the subjective, reinforcing, and cardiovascular effects of intravenously administered cocaine, caffeine, and nicotine were examined using double-blind procedures in nine volunteers with histories of using tobacco, caffeine, and cocaine. Each participant was exposed to two chronic drug maintenance phases (21 mg/day nicotine transdermal patch and placebo transdermal patch). Within each drug phase, the participant received intravenous injections of placebo, cocaine (15 and 30 mg/70 kg), caffeine (200 and 400 mg/70 kg), and nicotine (1.0 and 2.0 mg/70 kg) in mixed order across days. Subjective and cardiovascular data were collected before and repeatedly after drug or placebo injection. Reinforcing effects were also assessed after each injection with a Drug vs Money Multiple-Choice Form. Intravenous cocaine produced robust dose-related increases in subjective and reinforcing effects; these effects were not altered by nicotine maintenance. Intravenous caffeine produced elevations on several subjective ratings; nicotine maintenance did not affect these ratings. Under the placebo maintenance condition, intravenous nicotine produced robust dose-related subjective effects, with maximal increases similar to the high dose of cocaine; nicotine maintenance significantly decreased the subjective and reinforcing effects of intravenous nicotine. The results of the present study demonstrate that chronic nicotine maintenance produces tolerance to the effects of intravenous nicotine, but does not affect the subjective or reinforcing effects of cocaine or caffeine.     

Galantamine attenuates some of the subjective effects of intravenous nicotine and improves performance on a Go No-Go task in abstinent cigarette smokers: a preliminary report

Rationale

Galantamine (GAL), a reversible and competitive inhibitor of acetylcholinesterase, is used clinically in the treatment of Alzheimer's dementia. Some preclinical and clinical studies support the potential efficacy of cholinesterase inhibitors for smoking cessation, although their effects on the behavioral and physiological responses to nicotine have not been examined. The goal of this study was to characterize GAL's actions on multiple outcomes, including withdrawal severity and cognitive performance, as well as subjective and physiological responses to nicotine administered intravenously.

Methods

A total of 12 smokers participated in a double-blind, placebo-controlled, crossover study. Smokers had two 4-day treatment periods, assigned in random sequence, to GAL (8?mg/day) or placebo treatment. On day 4 of each treatment phase, smokers had an experimental session in which they received an intravenous (IV) dose of saline or 1?mg/70?kg nicotine, 1?h apart, in a random order.

Results

GAL attenuated the self-reported rating of ??craving for cigarettes?? and prevented decrements in performance in a Go/No-Go task. In response to IV nicotine, GAL treatment attenuated the self-report ratings of ??like the drug effects,?? ??good drug effects,?? ??bad drug effects,?? and ??stimulated.??

Conclusions

These findings support the potential utility of GAL as a treatment for smoking cessation.     

Comparing the physiological and subjective effects of self-administered vs yoked cocaine in humans

Rationale Studies with laboratory animals demonstrating different effects of self- vs experimenter-administered drug suggest that the ability to control or predict drug delivery may be an important determinant of drug action.Objective This study assessed whether self-administered and yoked cocaine injections produce different effects in humans.Methods Ten inpatient volunteers with experience in using cocaine participated in a double-blind, yoked design during which four experimental test sessions were conducted. During two sessions, participants controlled if and when up to six 40 mg/70 kg i.v. cocaine injections were given. During two sessions, participants received noncontingent exposure to the same pattern of injections given during the preceding session (i.e., yoked) under blind conditions. Sessions followed a fixed-order, ABAB design. Measures of subjective and physiological response to cocaine were taken throughout each session.Results Cardiovascular safety parameters were exceeded in some individuals after yoked, but not self-administered, cocaine resulting in some scheduled injections being delayed or withheld. Mean systolic and diastolic blood pressures were higher following yoked compared to self-administered cocaine. In contrast, analysis of the subjective effects revealed only small and generally nonsignificant differences in the effects of self-administered vs yoked cocaine.Conclusions These results suggest that under the laboratory methods employed, control over the schedule of drug delivery may not alter the subjective effects of cocaine in humans. In contrast, the cardiovascular effects of cocaine appear to be greater when the drug is administered noncontingently.     

Physiological, subjective and reinforcing effects of oral and intravenous cocaine in humans

RATIONALE: There is little comparative information on the qualitative similarity, relative potency and reinforcing effects of oral cocaine versus cocaine administered via other routes. METHODS: The present study used a within-subject, double-blind, double-dummy design to compare the physiological, subjective and reinforcing effects of placebo and oral (62.5, 125, 250 mg/70 kg) and intravenous (IV) (12.5, 25, 50 mg/70 kg) cocaine in volunteers with histories of cocaine abuse. RESULTS: Cocaine produced dose-dependent increases on heart rate and blood pressure, with effects lasting longer after oral than IV cocaine. Subjective ratings (e.g., "rush," "drug effect," "liking") were qualitatively similar and dose-dependently increased after oral and IV administration, and the duration of effects was similar under both routes. On a money versus drug choice measure of reinforcement, the monetary amounts at which participants chose drug over money increased as a function of cocaine dose under both routes of administration. At doses that produced comparable subjective, physiological, and reinforcing effects, oral cocaine was not identified as cocaine as frequently as IV cocaine. Across measures, the data suggested that IV cocaine was approximately 10 times more potent than oral cocaine. CONCLUSIONS: Overall, the results of this study support qualitatively similar effects of oral and IV cocaine and suggest that oral cocaine may be an effective tool for studying cocaine's effects in human laboratory studies.     

Mecamylamine reduces some EEG effects of nicotine chewing gum in humans

Spontaneous EEG was recorded in nine cigarette smokers who had been abstinent from tobacco for 12 hr. Subjects were treated with a capsule containing either centrally acting nicotine blocker, mecamylamine (10 mg), or placebo. At each of three 60-min intervals after the capsule was ingested, the subjects chewed two pieces of gum containing a total of 0, 4 or 8 mg of nicotine. Nicotine and mecamylamine dose combinations were randomized across subjects. Two three-minute periods of spontaneous EEG were recorded before the capsule and before and after gum chewing from bipolar electrode montages at the following positions: Cz-T5, Cz-T6, Cz-F7 and Cz-F8. During one period the subjects relaxed with eyes closed, in the other period they performed a math task with eyes open. When the drugs were given individually, mecamylamine decreased beta power and nicotine gum (4 and 8 mg) increased alpha frequency. Mecamylamine pretreatment prevented the increase in alpha frequency caused by the 4 mg gum dose but not the 8 mg dose. Alpha power was increased by the 8 mg gum dose and that increase was prevented by mecamylamine. Self-reported ratings of the "strength" of the gum were significantly diminished by mecamylamine pretreatment. The data are consistent with the results of earlier studies which indicate that the effects of tobacco administration and withdrawal are mediated by central actions of nicotine.     

Oral caffeine maintenance potentiates the reinforcing and stimulant subjective effects of intravenous nicotine in cigarette smokers

Abstract Rationale. Epidemiological, clinical and pre-clinical observations suggest that caffeine can potentiate the reinforcing and discriminative effects of nicotine. Objective. The present study examined whether chronic exposure to moderate doses of caffeine affects the reinforcing and subjective effects of intravenously administered nicotine. Methods. The effects of oral caffeine maintenance on the subjective and physiological effects of intravenously administered nicotine and caffeine were examined using double-blind methods in nine volunteers with current use of tobacco, caffeine, and cocaine. Each subject was exposed to two chronic drug phases (200 mg/70 kg oral caffeine t.i.d. and placebo t.i.d.), each of at least 12 days duration. Within each drug phase, the subject received intravenous injections of placebo, nicotine (1.0 and 2.0 mg/70 kg), and caffeine (200 and 400 mg/70 kg) in mixed order. Physiological and subjective data were collected before and repeatedly after drug or placebo injection. Results. Both intravenous nicotine and caffeine produced significant increases in ratings of drug effect, stimulated, rush, and bad effect, with only nicotine significantly increasing ratings of liking and good effect. Caffeine maintenance significantly increased ratings of drug effect and stimulated after the high dose of nicotine, and significantly decreased ratings of bad effect after the low dose of nicotine. Caffeine maintenance also significantly increased the identification of the low dose of nicotine as a stimulant. A drug versus money measure of reinforcement showed that subjects were willing to pay money to receive nicotine injections, but willing to forfeit money to avoid caffeine injections. Furthermore, subjects were willing to pay significantly more money to receive the high dose of nicotine in the caffeine maintenance phase than in the abstinence phase. Both intravenous nicotine and caffeine increased diastolic blood pressure and decreased skin temperature, and nicotine also increased heart rate. These physiological effects of intravenous nicotine and caffeine as well as the subjective effects of intravenous caffeine were not influenced by caffeine maintenance. Conclusions. The results extend recent clinical and preclinical findings by showing that oral caffeine maintenance can potentiate the reinforcing and stimulant subjective effects of nicotine. Electronic Publication     

The effects of fluoxetine on the subjective and physiological effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans

Objective The purpose of this study was to investigate the role of serotonin (5-HT) in the effects of oral 3,4-methylenedioxymethamphetamine (MDMA) in humans.Materials and methods The subjective and physiological effects of 1.5 mg/kg MDMA were evaluated after 20 mg fluoxetine in eight recreational MDMA users in a double-blind, placebo-controlled study. During phase 1, participants were maintained on placebo for at least 5 days and tested with MDMA and placebo on separate sessions. In phase 2, the procedure was the same except fluoxetine was administered daily for at least 5 days. During sessions, placebo or fluoxetine was given 1 h before the session drug and effects were measured over the next 7 h.Results MDMA increased positive-like subjective effects on all the Addiction Research Center Inventory scales; Arousal, Elation, Positive Mood, and Vigor on the Profile of Mood States; Drug Liking, Friendly, Good Drug Effect, High, Stimulated, and Talkative on the Visual Analog Scale; and End-of-Session Liking and Crossover Point on the Multiple Choice Procedure. MDMA also increased measures of anxiety. On the Hallucinogenic Rating Scale, all scales except Volition were increased. MDMA also increased blood pressure and heart rate. Fluoxetine treatment attenuated most of the positive-like subjective effects including the Affect and Soma scales of the Hallucinogen Rating Scale. In addition, heart rate but not blood pressure increases were reduced.Conclusions These results suggest that blockade of 5-HT reuptake by fluoxetine can dampen the effects of MDMA and further supports the role of 5-HT in its behavioral effects in humans.     

Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers

RATIONALE: The psychopharmacological profile of hydromorphone, an opioid that has been used extensively for many years for post-operative pain management, has not been adequately characterized in non-drug abusers. OBJECTIVES: To characterize the subjective, psychomotor, and physiological effects of a range of single doses of hydromorphone in non-drug-abusing volunteers and to compare the effects of hydromorphone with that of morphine, a benchmark mu opioid agonist. METHODS: Subjects in a six-session study were injected in an upper extremity vein with 0, 0.33, 0.65, 1.3 mg/70 kg hydromorphone, and 5 and 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. RESULTS: Hydromorphone increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of ("dry mouth", "flushing", and "nodding", and increased visual analog scale ratings indicative of both pleasant (e.g., drug liking) and unpleasant (e.g., "feel bad") effects. The subjective effects of morphine at putatively equianalgesic doses to those of hydromorphone were similar to those of hydromorphone, but in some cases of lesser magnitude. Psychomotor impairment was modest with hydromorphone and absent with morphine. Both opioids produced dose-dependent decreases in pupil size. A relative potency analysis indicated that hydromorphone was 10 times as potent as morphine (1 mg hydromorphone=10 mg morphine). CONCLUSIONS: The results of this study demonstrate that 0.33-1.3 mg hydromorphone had orderly, dose-related effects on subjective, psychomotor, and physiological variables, and similar effects to those of a benchmark mu opioid agonist, morphine.     

Melatonin treatment attenuates symptoms of acute nicotine withdrawal in humans

Nicotine withdrawal is typically associated with negative changes in mood and performance, which often lead to relapse. We tested whether an oral 0.3-mg dose of melatonin administered 3.5 h after the nicotine withdrawal, and increasing circulating melatonin concentrations within the physiological range, affects the symptoms of acute 10-h (0800-1800 h) nicotine withdrawal in regular smokers. Self-reported ratings of mood, sleepiness, and cigarette craving were assessed hourly, using 17 visual analog scales (VAS). Computerized Four-Choice Reaction Time (FCRT) and Simple Auditory Reaction Time (SART) tests were used to assess performance every 2 h. Saliva samples were collected hourly, and salivary melatonin levels were measured using supersensitive radioimmunoassay. Compared with the placebo, melatonin treatment significantly reduced self-ratings of "anxious," "restless," "tense," "irritable," "angry," "depressed, " "impatient," and "craving for cigarettes." Melatonin treatment did not significantly change the responses on the performance tests used. These data suggest that melatonin can help to counteract the acute effects of smoking cessation on mood.     

Depressive symptoms modulate the subjective and physiological response to cocaine in humans

The goal of this study was to examine the relationship between the presence of subclinical depressive symptoms and physiological and subjective responses to smoked cocaine in humans. Cocaine users without major depression, who participated in various inpatient studies, received a single 0.4 mg/kg of smoked cocaine. When the relationship between the Beck Depression Inventory (BDI) scores and various subjective and physiological responses to cocaine was examined, similar trends were found. Low BDI scores of 0-7 were associated with a smaller physiological and subjective cocaine response. In contrast, BDI ranges of 8-13 were associated with enhanced cocaine response which plateaued or declined in the higher (> 14) BDI group. These group differences were not explained by sex or body weight differences among groups. The implication of these results is that the presence of depressive symptoms may affect cocaine use behavior partly by being associated with an enhanced response to cocaine.     

Reinforcing and subjective effects of methylphenidate in humans

This study assessed the reinforcing and subjective effects of methylphenidate in a group of 35 adults (15 females and 20 males) with no history of drug dependence. A discrete-trial choice procedure was used to assess the reinforcing effects of a single oral dose of methylphenidate selected to produce a moderate subjective response in each subject (range 20-40mg). A number of variables (gender, current and past drug use, personality, and baseline mood and arousal) were examined in an attempt to identify sources of variability in drug response. Methylphenidate was chosen on 28% of occasions. In the group as a whole, methylphenidate had no effect on ratings of drug liking, but did increase ratings indicative of "positive" mood, CNS stimulation and anxiety. Within-subject variability in methylphenidate choice was related to variability in subjective response to the drug across choice trials. Methylphenidate choice was also associated with between-subject differences in prior opioid use and several personality dimensions. When compared with the results of a prior study of the same design with d-amphetamine, these results suggest that methylphenidate produces a somewhat different profile of subjective effects, and may be a less efficacious reinforcer than d-amphetamine.     

Pharmacokinetics and subjective effects of 1P‐LSD in humans after oral and intravenous administration

1‐Propanoyl‐lysergic acid diethylamide (1P‐LSD) appeared as a non‐controlled alternative to LSD a few years ago. Although evidence is beginning to emerge from in vitro and animal studies that 1P‐LSD might serve as a prodrug for LSD, an equivalent evaluation in humans is unavailable. Controlled oral and intravenous self‐administrations of 100 μg 1P‐LSD hemitartrate are reported in two human volunteers followed by analyses of urine and serum samples using a fully validated LC–MS/MS method. Psychometric evaluations included assessment of selected subjective drug effects and administration of the Five‐Dimensions of Altered States of Consciousness rating scale (5D‐ASC). In serum and urine, oral administrations of 1P‐LSD only led to the detection of LSD reflecting biphasic elimination with a terminal elimination half‐life of approx. t_1/2 = 6.4 h. 1P‐LSD could be detected for only up to 4.16 h in serum and 2.7 h in urine following intravenous administration, whereas LSD was detected in all serum samples (last sampling after approx. 24 h) and up to 80 h in urine. LSD showed first order elimination kinetics with an approx. t_1/2 = 5.7 h, whereas 1P‐LSD showed a rapid decrease in concentration within the first hour followed by a slower decrease, most probably due to hydrolysis. The bioavailability of LSD after oral ingestion of 1P‐LSD was close to 100%. The psychosensory effects of 1P‐LSD and their time course were comparable to those seen after uptake of LSD in other studies which further supports the prodrug hypothesis. The 5D‐ASC scores were higher after oral compared with intravenous administration of 1P‐LSD.     

Nicotine alters some of cocaine's subjective effects in the absence of physiological or pharmacokinetic changes.

Tobacco smoking and cocaine use often co-occurs and the frequency of smoking has been positively correlated with the likelihood of cocaine use. In addition, nicotine pretreatment has been shown to increase the rate of cocaine self-administration in rats and to enhance cue-induced cocaine craving in humans. The present study was conducted to investigate whether nicotine pretreatment via a transdermal patch alters the behavioral, physiological, and pharmacokinetic effects of an acute dose of cocaine in nondependent human volunteers. Seven male tobacco smokers who used cocaine occasionally provided informed consent and participated in this placebo-controlled, four-visit study. Following pretreatment with a transdermal nicotine patch (placebo, 14 mg), subjects were challenged with an acute dose of intranasal cocaine (placebo, 0.9 mg/kg). Nicotine pretreatment attenuated cocaine-induced increases in reports of "high" and "stimulated" and increased the latency to detect cocaine effects and cocaine-induced euphoria. Nicotine did not alter cocaine's effects on heart rate, skin temperature, and blood pressure or plasma cocaine, benzoylecgonine (BE), or ecgonine methylester (EME) concentrations. Our findings indicate that nicotine pretreatment alters some of the positive subjective effects of cocaine in humans without affecting cocaine's effects on physiologic responses or pharmacokinetic profiles.     

Sex differences in the subjective and reinforcing effects of cigarette nicotine dose

RATIONALE: Some research with novel nicotine delivery methods suggests that nicotine itself may be less reinforcing in women than in men. However, sex differences in the reinforcing effects of nicotine dose via cigarette smoking have received little attention. OBJECTIVES: Sex differences in the subjective and reinforcing effects of smoking were examined as a function of two cigarette nicotine "dose" levels (moderate - subjects' preferred brand, > or = 0.7 mg yield; low - Carlton "ultra-light", 0.1 mg yield). METHODS: Male and female smokers ( n = 30) participated in three sessions, the first two involving independent assessment (only one brand available), and the third involving concurrent assessment (both brands available), of subjective ratings (e.g. "liking") and reinforcement for the two cigarette brands. Subjects were blind to the brand of each cigarette, and subjects abstained overnight prior to each session. Reinforcement was determined by responses on a computer task to earn single puffs on the designated cigarette. RESULTS: Subjective ratings differed between the low versus moderate cigarette nicotine dose under both independent and concurrent assessment conditions, as expected. Notably, this dose difference was smaller in women than in men (i.e. significant sex by dose interactions). The dose effect on smoke reinforcement also was smaller in women than men, but only under the independent and not concurrent assessment condition. CONCLUSIONS: These results indicate that cigarette nicotine dose is a less important influence on the subjective and, under some conditions, reinforcing effects of smoking in women than in men.     

Varenicline blocks nicotine intake in rats with extended access to nicotine self-administration

Rationale

Much evidence indicates that individuals use tobacco primarily to experience the psychopharmacological properties of nicotine. Varenicline, a partial ??4??2 nicotinic acetylcholine receptor (nAChR) agonist, is effective in reducing nicotine craving and relapse in smokers, suggesting that ??4??2 nAChRs may play a key role in nicotine dependence. In rats, the effect of varenicline on nicotine intake has only been studied with limited access to the drug, a model of the positive reinforcing effect of nicotine. Varenicline has not been tested on the increase in motivation to take nicotine in nicotine-dependent rats.

Objectives

The present study evaluated the effects of varenicline on nicotine intake in rats with extended access to nicotine self-administration (23?h/day), a condition leading to the development of nicotine dependence. We hypothesized that varenicline??s effects on nicotine self-administration would be greater in rats with extended than limited access to the drug and after forced abstinence rather than during baseline self-administration.

Results

Varenicline dose-dependently decreased nicotine self-administration in rats with limited (1?h/day) and extended (23?h/day) access. Despite an increased sensitivity to the motivational effects of abstinence on nicotine intake compared with limited-access rats, varenicline was equally effective in decreasing nicotine intake in dependent rats with extended access to nicotine.

Conclusion

These results suggest that ??4??2 nAChRs are critical in mediating the positive reinforcing effects of nicotine but may not be a key element underlying the negative reinforcement process responsible for the increased nicotine intake after abstinence in dependent subjects.     

Reinforcing, subjective, and physiological effects of MDMA in humans: a comparison with d-amphetamine and mCPP

3,4-methylenedioxymethamphetamine (MDMA) is a widely used drug of abuse chemically related to both the amphetamines and mescaline. Laboratory animal studies have shown that MDMA is a potent re-uptake inhibitor and releaser of dopamine and serotonin. Although the subjective and physiological effects of MDMA have been compared to d-amphetamine in humans, no direct comparison with a serotonin releasing agent has been reported and reinforcing effects have not been evaluated. In this paper we report a direct comparison of the reinforcing, subjective, and physiological effects of MDMA (1 and 2 mg/kg) to d-amphetamine (10 and 20 mg), to metachlorophenylpiperazine (mCPP--a serotonin releasing agent (0.5 and 0.75 mg/kg)), and to placebo using a within-subject design in 12 volunteers with moderate MDMA experience. Both the high dose of d-amphetamine and MDMA showed significant reinforcing effects as indicated by high cross-over values on the multiple choice procedure compared to all other treatments. All three drugs showed dose-dependent changes in subjective effects whereas physiological effects were most pronounced for MDMA with almost no changes seen with mCPP. The subjective effects of MDMA were similar both to those of mCPP and d-amphetamine, suggesting that both dopamine and serotonin systems are involved in mediating these effects. In contrast, only the dopaminergic agents, d-amphetamine and MDMA, had reinforcing effects.